REGULATION OF HOX GENE EXPRESSION IN HUMAN BREAST CANCER

维甲酸(RA)对许多细胞过程有深远的影响， 包括胚胎形态形成和细胞分化。Ra可以 还调节多种癌前病变的生长和分化 和肿瘤细胞类型。最近的研究表明，类风湿关节炎具有抗血管紧张素转换酶活性。 乳腺癌细胞的致瘤和生长抑制作用 在各种其他类型的癌症中，包括鳞癌 头颈部和子宫颈的癌。尽管完全相同的 维甲酸作为形态原、致畸剂、 和一种抗肿瘤药物还不清楚，一些基因是 在分化诱导和分化过程中受RA调节 胚胎发生。其中一个基因HOXA-1是同源异型盒基因的成员 一家人。Hoxa-1首先从RA-1的cDNA文库中分离出来。 处理后的F9小鼠胚胎癌细胞株。HOXA-1基因的表达 RA以不依赖蛋白质合成的方式上调基因 提示HOXA-1基因是RA的主要靶基因。 此外，在该基因的3‘端发现了一个RA反应增强子。 HOXA-1基因，这种RA反应增强子与在 RAR-β基因。这些发现表明，RA直接调节 至少一个同源异型盒基因的转录，HOXA-1。最近， 几个研究小组报告说，在这两个组织中，Hoxa-1的表达都异常高 人乳腺癌细胞系和小鼠乳腺肿瘤。它还 研究表明，维甲酸仅能抑制人乳腺癌的细胞生长 拥有功能性雌激素受体的细胞系。目前还不清楚 Hoxa-1基因在乳腺癌细胞中是如何调控的，以及 Hoxa-1基因异常表达与Hoxa-1基因的表达 雌激素受体在恶性乳腺上皮细胞中的表达 在这项提案中，我计划研究HOXA-1基因的调控 在乳腺癌细胞中的表达。具体地说，我将：L)审查 Hoxa-1基因在正常与恶性乳腺上皮细胞中的表达(2) 确定HOXA-1基因的基因组调控序列 在乳房中异常高表达的与之相关的或需要的 癌细胞系，3)定义精确的调控序列， Hoxa-1基因在乳腺中的异常表达 肿瘤细胞株，4)研究其表达的调节 乳腺肿瘤转基因小鼠模型系统中HOXA-1基因的表达 发展。这些实验应该为我们提供对 乳腺癌细胞中HOXA-1基因的调控。

Retinoic acid (RA) exerts profound effects on many cellular processes, including embryonic pattern formation and cellular differentiation. RA can also regulate the growth and differentiation of a variety of pre-malignant and neoplastic cell types. Recent studies have shown that RA exerts anti- tumorigenic and growth inhibitory effects both in mammary carcinoma cell lines, and in a variety of other types of cancers, including squamous carcinoma of the head and neck, and of the cervix. Although the exact mechanisms by which retinoic acid can function as morphogen, a teratogen, and an anti-tumorigenic agent are not understood, a number of genes are regulated by RA during the induction of differentiation and during embryogenesis. One such gene Hoxa-1, is a member of the homeobox gene family. Hoxa-1 was first isolated from a cDNA library made from an RA- treated F9 murine embryonic carcinoma cell line. Expression of the Hoxa-1 gene is up-regulated by RA in a protein synthesis-independent fashion which indicates that the Hoxa-1 gene is a primary target gene of RA. Moreover, an RA-responsive enhancer was identified in the 3' region of the Hoxa-1 gene, and this RA responsive enhancer is identical to that found in the RAR-beta gene. These findings indicate that RA directly regulates the transcription of at least one of the homeobox genes, Hoxa-1. Recently, several groups have reported abnormally high Hoxa-1 expression in both human breast carcinoma cell lines and mouse mammary tumors. It has also been shown that RA can inhibit cell growth only in human breast carcinoma cell lines which possess a functional estrogen receptor. It is not clear how the Hoxa-1 gene is regulated in the breast carcinoma cells, and whether there is any correlation between aberrant Hoxa-1 expression and expression of estrogen receptor among malignant breast epithelial cells. In this proposal, I plan to investigate the regulation of Hoxa-1 gene expression in breast carcinoma cells. Specifically, I will: l) examine the Hoxa-1 gene expression in normal vs. malignant breast epithelial cells, 2) determine the genomic regulatory sequences of the Hoxa-1 gene that are involved in or required for its aberrantly high expression in breast cancer cell lines, 3) define the precise regulatory sequences that are involved in the aberrant expression of the Hoxa-1 gene in the breast cancer cell lines, 4) investigate the regulation of the expression of the Hoxa-1 gene in a transgenic mouse model system for breast tumor development. These experiments should provide important insights into the regulation of the Hoxa-1 gene in breast cancer cells.